CH513910A - Thiazole derivs. analgesics, antipyretics, antiinflammatories - Google Patents

Abstract

(A) Compds. of general formula (I): - X= H or (1-3C) alkyl - Y= Ph opt. subst. by one or two hal., and z= - where R'=H, an alkali metal, (1-3c) alkyl, (3-5c) dialkylaminomethyl, N-piperidinomethyl or N-morpholinomethyl. - R2 and R3 = H or (1-3c) alkyl, but if R2=R3= H, R'=H or (1-3c) alkyl. - Y or Z is in the 2 postn. - (B) Salts of I. - Anti-inflammatories, anti-pyretics, and analgesics. - Br2(0.8g.) in AcOH (10 ml.) was added (10 mins.) to dimethyl 2-(4-chlorophenyl) thiazol-4-yl-malonate (1.6 g.) and NaOAc (0.82g.) in AcOH (20 ml.) at 20 deg., stirred 30 mins., poured into H2O (100 ml.), extd. with Et2O (50 ml.), dried over MgSO4, evapd., and recryst. from cyclohexane, giving dimethyl alpha-bromo-alpha(2-(4-chlorophenyl) thiazol-4-yl) malonate, m.p. 110-111 deg.

Description

  

  Process for the production of new thiazole derivatives The invention relates to a process for the production of new thiazole derivatives with anti-inflammatory, analgesic and antipyretic properties.



  The products of the process correspond to the formula in one of their tautomeric forms:
EMI0001.0000
    Ver bond l in which X is hydrogen or an alkyl radical with a maximum of 3 carbon atoms, Y is the phenyl radical or a substituted phenyl radical with a maximum of two halogen atoms selected from fluorine, chlorine and bromine, R1 is hydrogen or an alkyl radical with a maximum of 3 carbon atoms and R2 and R3, which are identical to or different from one another, each represent an alkyl radical having a maximum of 3 atoms.



  The pharmaceutically acceptable salts of such compounds are also produced.



  It is to be understood hereinafter that when represents a hydrogen atom, the compounds may exist primarily in the 44-thiazoline tautomeric form. For the sake of simplicity, all process products are called thiazole derivatives in this description.



  X or R1 can e.g. B. represent a hydrogen atom or a methyl radical; R2 or R3 can e.g. B. represent a methyl or ethyl radical.



  If the thiazole derivative is sufficiently basic, non-toxic, pharmaceutically acceptable acid addition salts are suitable. A preferred one obtainable in accordance with the process is? - [4- (4-bromophenyl) thiazol-2-yl-?

  -methylmalonic acid dimethyl ester. The inventive method consists in that one means possessing a compound of the formula
EMI0001.0011
    in which X and Y have the above meaning and Hal in which X and Y have the above meaning, a chlorine, bromine or iodine atom, with a malonic acid diester of the formula
EMI0001.0013
    in which R1, R2 and R3 have the above meaning and M is an alkali metal, and the ester obtained is converted into a pharmaceutically acceptable acid addition salt, if necessary.



  M can represent a sodium or potassium atom, for example. The reaction can be carried out in one of the corresponding malonic acid diesters and / or in an inert solvent, e.g. B. dimethylformamide can be carried out. It can be accelerated or completed by adding heat.



  The pharmaceutically acceptable salts can be prepared in a manner known per se.



  The invention will now be explained in more detail with reference to execution examples. <I> Example 1 </I> First, a 500 / o suspension of sodium hydride in mineral oil is prepared and washed free of mineral oil by decanting with petroleum ether. 6 ml of diethyl malonate are added to 1.9 g of this suspension in 25 ml of dry dimethylformamide and the mixture is stirred for 30 minutes. 5.4 g of 2-bromo-4- (4-bromophenyl) thiazole are then added.

   The mixture is heated with stirring in an oil bath maintained at 145 to 155 ° C. for 4 hours. First 50 ml of water and then enough hydrochloric acid are added to the cooled mixture to bring the pH to 7, and the solid matter that has been precipitated is separated off by filtration and washed successively with 40 ml of water and 50 ml of ether to remove colored impurities to remove. The residue is dissolved in 100 ml of methylene chloride and the solution is washed successively with 30 ml of 10% strength aqueous sodium carbonate solution and 30 ml of water.

    The solution is dried over anhydrous sodium sulfate, decolorized with animal charcoal, filtered and evaporated to dryness.



  After recrystallization twice from ethanol, the 4- (4-bromophenyl) thiazol-2-ylmalonic acid diethyl ester with a melting point of 130 ° -131 ° C. is obtained.



  The following compounds can be obtained in a similar manner using the corresponding starting materials: 4- (4-bromophenyl) thiazol 2 ylmalonic acid dimethyl ester, mp 173-174 C (after recrystallization from chlorobenzene); 5- (4-chlorophenyl) thiazol-2-ylmalonic acid dimethyl ester, mp 212.5-214 ° C. (after recrystallization from chlorobenzene); 5- (4-chlorophenyl) thiazol-2-ylmalonic acid diethyl ester mp 161-161.5 C (after recrystallization from n-propanol); and α - [5- (4-chlorophenyl) thiazol-2-yl] - α-methylmalonic acid dimethyl ester, m.p. 129-130 C (after recrystallization from acetonitrile).

    <I> Example 2 </I> Diethyl α-methylmalonate (3.5 g) was added to a suspension of sodium hydride (0.96 g, 50% dispersion - treated as in Example 1) in dry dim thylformamide (12 ml) was added and the mixture was stirred at room temperature until the evolution of hydrogen had ceased. 2-Bromo-4- (4-bromophenyl) thiazole (3.2 g) was added and the mixture was stirred on an oil bath at 110 ° C. for 1.5 hours. The solution was cooled, diluted with water (50 ml) and extracted several times with methylene chloride (3 x 50 ml).

   The extract was washed with water (3 × 30 ml), dried over anhydrous sodium sulphate and evaporated, and the resulting oil was subjected to thin-layer chromatography on silica with evolution by means of benzene. Elution of the corresponding band with ether and evaporation gave α- [4- (4-bromophenyl) -thiazol-2-yl] - -methylmalonic acid diethyl ester, which was recrystallized from petroleum ether (bp 40-60 ° C.). The bond melted at 45-46 C.



  In a similar way, using the corresponding starting materials, the α- [4- (4-bromophenyl) thiazol-2-yl] - yl] - α-methylmalonic acid dimethyl ester of m.p. 64 -65.5 C after recrystallization from petroleum ether (from Bp. 60-80 C).

 

Claims (1)

PATENT CLAIM Process for the preparation of thiazol-2-yl-malonic acid esters, which in one of its tautomeric forms has the formula EMI0002.0033 have, in which X is hydrogen or an alkyl radical with a maximum of 3 carbon atoms, Y is the phenyl radical or a substituted phenyl radical with a maximum of two halogen atoms selected from fluorine, chlorine and bromine, R1 is hydrogen or an alkyl radical with not more than 3 carbon atoms and R2 and R3, which are identical or different from one another, each represent an alkyl radical with at most 3 carbon atoms, as well as their pharmaceutically acceptable acid addition salts, characterized in that a compound of Farmei EMI0002.0040 in which X and Y have the above meaning and Hai means a chlorine, bromine or iodine atom, with a malonic acid residue of Farmei EMI0002.0043 in which Rl, R2 and R3 have the above meaning and M is an alkali metal, converts and the ester obtained he optionally converted into a pharmaceutically acceptable acid addition salt.